Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation
| Autor: | Maximiliano G. Gutierrez, Francisco J. Salguero, Stephen V. Gordon, Christophe J. Queval, Morgane Mitermite, Esen Wooff, Laura Schnettger, Dirk Werling, Alicia Smyth, Waldo L. García-Jiménez, Bernardo Villarreal-Ramos, Matthias Trost, Laure Botella, Tiaan Heunis, Antony Fearns |
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| Rok vydání: | 2021 |
| Předmět: |
Host tropism
Pathology and Laboratory Medicine Giant Cells White Blood Cells 0302 clinical medicine Animal Cells Medicine and Health Sciences Macrophage Biology (General) Pathogen Mammals Staining 0303 health sciences Mycobacterium bovis Eukaryota Cell Staining Ruminants Specimen preparation and treatment 3. Good health Actinobacteria Intracellular Pathogens Mycobacterium tuberculosis complex Vertebrates Host-Pathogen Interactions Granulomas Cellular Types Pathogens Research Article Imaging Techniques QH301-705.5 Immune Cells Immunology Biology Microbiology Mycobacterium tuberculosis 03 medical and health sciences Bovines Virology Fluorescence Imaging Genetics Animals Humans Tuberculosis Molecular Biology 030304 developmental biology Blood Cells Bacteria Macrophages Intracellular parasite Organisms DAPI staining Biology and Life Sciences Cell Biology RC581-607 biology.organism_classification Research and analysis methods Viral Tropism Giant cell Amniotes Nuclear staining Cattle Parasitology Immunologic diseases. Allergy Zoology 030217 neurology & neurosurgery |
| Zdroj: | PLoS Pathogens, Vol 17, Iss 3, p e1009410 (2021) PLoS Pathogens |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1009410 |
| Popis: | The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M. tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. The host and pathogen determinants underlying host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection, and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed blood-derived primary human and bovine macrophages (hMϕ or bMϕ, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hMϕ whereas both Mbv and Mtb efficiently replicate in bMϕ. Specifically, we show that out of the four infection combinations, only the infection of bMϕ with Mbv promoted the formation of multinucleated giant cells (MNGCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bMϕ promote macrophage multinucleation. Importantly, we extended our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNGCs. Our findings implicate MNGC formation in the contrasting pathology between Mtb and Mbv for the bovine host and identify MPB70 from Mbv and extracellular vesicles from bMϕ as mediators of this process. Author summary The identification of host and pathogen factors contributing to host-pathogen interaction is crucial to understand the pathogenesis and dissemination of tuberculosis. This is particularly the case in deciphering the mechanistic basis for host-tropism across the MTBC. Here, we show that in vitro, M. bovis but not M. tuberculosis induces multinucleated cell formation in bovine macrophages. We identified host and pathogen mechanistic drivers of multinucleated cell formation: MPB70 as the M. bovis factor and bovine macrophage extracellular vesicles. Using a cattle experimental infection model, we confirmed differential multinucleated cell formation in vivo. Thus, we have identified host and pathogen factors that contribute to host tropism in human/bovine tuberculosis. Additionally, this work provides an explanation for the long-standing association of multinucleated cells with tuberculosis pathogenesis. |
| Databáze: | OpenAIRE |
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